Ionic chitosan -iodine complexes : antiseptic hydrogels and wound healing promoters

ABSTRACT

This invention describes non-staining, pharmaceutically useful compositions of ionic complexes made between the cationic polymer chitosan or its derivatives and the small anionic iodine-iodide complex (ICIC&#39;s). Unlike previously disclosed ion transfer chitosan iodine complexes, ICIC&#39;s were found to possess dramatically higher viscosity than those of each ingredient separately, and instantly form a gel structure that is easily dispersible upon shaking. In addition to their antiseptic power, ICIC&#39;s showed better skin biocompatibility than povidone iodine and effectively promoted wound healing.

FIELD OF THE INVENTION

[0001] This invention is related to ionic complexes of iodine withchitosan or its derivatives, methods of preparation thereof andpharmaceutically useful compositions containing these complexes. Thisinvention is also related to hydrogels made of chitosan-iodine ioniccomplexes. This invention further relates to methods of treatments bythese preparations, and their use in promoting wound healing and asantiseptics.

BACKGROUND OF THE INVENTION

[0002] Wounds are internal or external bodily injuries or lesions causedby physical, chemical, microbial, or thermal means. Natural woundhealing involves a series of three processes:

[0003] a. An inflammation phase where platelet aggregation and clottingoccur to stop bleeding and induce influx of various types of cells tostart a cellular proliferation process;

[0004] b. A cellular proliferation phase where new connective orgranulation tissue is formed; and

[0005] c. A remodeling phase where the granulation tissue is replaced bycollagen and elastin fibers forming a scar.

[0006] The primary step in wound treatment is to prevent or eliminatemicrobial contamination of wounds by using disinfectants or antiseptics.Since contaminating microbes release toxins and cause pathologicalchanges at the wound site, delaying the natural healing process, the useof antimicrobials is an essential first step in wound treatment.

[0007] Among antimicrobials, iodine in its elementary state exhibits auniversal germicide activity against bacteria, fungi, and viruses andfor this reason has been used in alcoholic solutions for decades.However, the limits to this use are the low stability of iodinesolutions, its notable aggressiveness on tissues when applied as asolution, and the persistent staining it leaves on applied tissues.

[0008] More recently, water soluble forms of iodine (known as iodophors)have been commercialized which only partially reduced these undesirableside effects. The most common employed iodophor ispolyvinylpyrrolidone-iodine, (also known as povidone iodine). Povidoneiodine is used for pre-operative skin disinfections, wounddisinfections, and as a mouthwash and vaginal antiseptic. However, inwound treatment, povidone iodine does not effectively promote good woundhealing. In fact, it either impaired wound healing or reduced woundstrength. (Kramer, J. Vasc. Nurs. 1999 March: 17(1) 17-23). In addition,povidone iodine showed negative effects on wound healing, similar tothose of steroids (Kashyap et al., Am. Surg. 1995 June; 61(6) 486-491).

[0009] A few attempts to prepare iodine-containing compositions tomitigate the adverse effects of both elemental iodine and povidoneiodine were made, using chitosan and its derivatives. See U.S. Pat. Nos.4,275,194 and 5,538,955)

[0010] Chitosan is a cationic polysaccharide obtained by deacetylationof the natural polymer chitin. Kato et al. (U.S. Pat. No. 4,275,194)have described a process to prepare chitosan iodine adducts for adisinfectant and a deodorant use. The process involved many days ofimpregnation and drying and the final product was recovered in the formof dry dark brown powder. The mentioned method failed to provide acommercially feasible way for production and use, due to the extensivetime periods required for preparation and the inconvenient non-liquidform of the product.

[0011] Because chitosan and derivatives have been recognized for theirwound healing activity, DeRosa et al. (U.S. Pat. No. 5,538,955) havedescribed different procedures to prepare solid forms of chitosan-iodineproducts. Those procedures required the use of elevated temperatures,special reactors for hazardous iodine gas, and took up to 5 days tocomplete. The resultant solid product took one to two days to dissolvein a suitable liquid. DeRosa et al. also suggested a liquid chitosaniodine preparation using high concentrations of surfactants. Becausesurfactants are known for their ability to dissolve or modify naturalcell lipid membranes, they can damage the protective barrier nature ofthe skin, causing skin tissue destruction and delayed wound healing.

[0012] Despite the fact that chitosan iodine products have been proposedfor more than twenty years, a clinically and pharmaceutically acceptableliquid formulation is yet to be established. It is the purpose of thisinvention to disclose a practical, fast and efficient method ofpreparing chitosan iodine liquid preparations that will eliminate theabove mentioned limitations of iodine, povidone iodine and previouslydisclosed chitosan iodine compositions.

[0013] This invention also has superior utility in promoting woundhealing without the need of additional medications such as growthfactors (Drohan et al, U.S. Pat. No. 6,124,273) or immobilized heparin(Kratz et al., Scand. J. Plast. Reconstr. Surg. Hand Surg. 1997). In theprior art formulations, such medications or supplements were required toovercome the limited efficiency of chitosan when used as a sole woundhealing promoter.

SUMMARY OF THE INVENTION

[0014] It is the object of this invention to provide liquid chitosaniodine compositions suitable for treatment of wounds by acting asantiseptics and a wound healing promoters. Another object of thisinvention is the formation of said useful compositions as ioniccomplexes between positively charged chitosan molecules in solution andthe solution of the small anionic iodine-iodide complexes (will bereferred to as ionic chitosan iodine complex or ICIC's). A furtherobject of this invention is the preparation of said compositions withoutthe need of heat, special reactors, surfactants or volatile solvents,such as alcohol. A further object of this invention is a composition ofICIC's formulated as a hydrogel and the use thereof to promote woundhealing.

DESCRIPTION OF THE INVENTION

[0015] In accordance with the present invention, it has been discoveredthat, unlike previously disclosed iodine based compositions, identifiedas adducts or charge transfer complexes, ICIC's were found to possessdramatically higher viscosity and instantly form a gel structure thateasily disperses upon shaking. A further discovery is that the color ofICIC's is dark purple which is easily distinguished from the dark brownor orange yellow colors of other chitosan iodine complexes. A yetfurther advantage of this invention is that treatment with thecompositions of the invention results in fast wound healing, minimalscar formation. Furthermore, permanent staining of the skin does notoccur.

[0016] In one embodiment, this invention provides a composition ofmatter comprising an ionic complex between cationic chitosan moleculesin solution and a monovalent, anionic small complex made ofiodine-iodide (I₃ ⁻). A second embodiment of this invention involves theexistence of ICIC in a hydrogel form suitable for direct application tointact or wounded skins of animals or humans. A third embodiment of thisinvention involves the formation of such complex in a homogeneoushydrogel form, without the need of any additional polymers or thickeningagent. A fourth embodiment of this invention involves casting ICIChydrogel into solid powder or flexible films or otherwise suitable filmsor sheets or the like.

[0017] The pharmaceutical compositions of this invention include,without limitation:

[0018] 1. Chitosan, or derivative, having an average molecular weightbetween 10 to 1000 kilo Daltons, preferably in the range of 100-800 kiloDaltons, and most preferably in the range of 250 to 750 kilo Daltons.The degree of deacetylation of chitosan is 40% to 95%, preferably 60% to90%.

[0019] 2. An aqueous vehicle that may include:

[0020] a. An acid from the group of acetic, lactic, citric, glycolic,and the like, or their buffers or salts, at a concentration resulting inpH values of the final composition between 3.0 and 8.0, more preferablybetween 4.0 and 7.0.

[0021] b. A low molecular-weight diol, such as ethylene or propyleneglycol, a triol such as glycerol, or a polyol such as sorbitol orpolyethylene glycol, at a concentration range between 5% and 25%.

[0022] 3. Elemental iodine at the concentration range of 0.05% to 5.0%,preferably at the concentration range of 0.1% to 1%.

[0023] 4. An iodide source such as potassium iodide, sodium iodide, orzinc iodide or the like, at a concentration range of 0.05% to 5%,preferably at a concentration range of 0. 1% to 1.0%, or hydroiodic acidof similar concentrations.

[0024] In this invention, the low-molecular weight dial, trial, orpolyol functions as a “non-volatile” compound. As used herein, theexpression “non-volatile” means having a boiling point equal to orgreater than the boiling point of ethylene glycol, that is, greater thanor equal to 198° C.

[0025] It has been discovered that the compounding order of the abovecomposition is very critical and has to be performed so that both thecationic polymer and the iodine-iodide complex are prepared in separateportions of the aqueous vehicle prior to final mixing.

[0026] An advantageous feature of this invention is the instantformation of ICIC in a gel form following the mixing of the cationic andanionic components. The formed gel will provide utmost physicalstability of the product during storage, yet can easily be transformedinto pourable fluid upon gentle shaking. The pourable fluid form has theadvantage of easily spreading on wounds or skin without the need ofrubbing. Another advantage of this invention is that, once ICIC's stayin contact with tissues, they transform back to a protective flexiblefilm that will protect the wound from the surrounding environments, andslowly release active iodine for disinfecting the tissue.

[0027] The formed protective film can also control oxygen permeabilityto the wound and eliminate the need of using occlusive bandages. Theformed film can also prevent the need for frequent wound treatments,which are usually painful. Another advantage of ICIC hydrogel is theirability to be cast and dried into flexible sheets or films that canserve as self-medicated bandages. Such bandage can absorb wounddischarge, accelerating wound repair. A further advantage of these driedfilms is they can be naturally degraded by tissue enzymes without theneed to remove them.

[0028] The following examples further illustrate the composition and useof this invention and are not intended to be limiting.

EXAMPLE 1

[0029] A 100 ml solution of ICIC was made, consisting of:

[0030] a. 0.8% chitosan (molecular weight of 650 kilo Daltons, 90%deacetylation degree);

[0031] b. 0.8% acetic acid; c. 1% potassium iodide;

[0032] d. 1% iodine; and

[0033] e. 10% glycerol.

[0034] Chitosan was dissolved in acetic acid, while potassium iodide andiodine were dissolved in a separate aqueous medium. Glycerol was thenadded to the iodine iodide mixture. Finally, chitosan solution was mixedwith the iodine containing liquid. The formed composition was a darkpurple, highly viscous, structured hydrogel that becomes thin fluid uponshaking.

EXAMPLE 2

[0035] A 100 ml solution of ICIC was made, consisting of:

[0036] a. 1.8% chitosan (molecular weight 100 Kilo Daltons, 90%deacetylation degree);

[0037] b. 1.8% acetic acid;

[0038] c. 0.4% potassium iodide;

[0039] d. 0.4% iodine.

[0040] Chitosan was dissolved in acetic acid, while potassium iodide andiodine were dissolved in a separate aqueous medium. Glycerol was thenadded to the iodine iodide mixture. Finally, chitosan solution was mixedwith the iodine containing liquid. The formed composition was a darkpurple, highly viscous, structured hydrogel that becomes thin fluid uponshaking.

[0041] The following references, all of which are incorporated herein byreference, are included so that the invention may be more fullyunderstood and practiced. The following references are not intended tobe limiting.

REFERENCES

[0042] U.S. Patent Documents 5,129,877 Gallo et al. July 1992 5,902,798Gouda et al. May 1999 5,620,706 Dumitriu et al. April 1997 5,836,970Pendit November 1998 6,150,581 Jiang et al. November 2000 4,275,194 Katoet al. June 1981 5,538,955 DeRosa et al. July 1996 6,124,273 Drohan etal. September 2000

OTHER REFERENCES

[0043] Hassan et al., J. Drug Targeting, 1:7-14, 1993.

[0044] Hassan et al., Pharm.Res., 7: 491-495, 1990

[0045] Shu et al., Int. J. Pharm., 15:201(1):51-58, 2000

[0046] Kramer, J. Vasc. Nurs., 1999 March: 17(1) 17-23

[0047] Kashyap et al., Am. Surg., 1995 Jun; 61(6) 486-491

[0048] Takeuchi et al., Pharm. Res., 17:94-99, 2ooo

[0049] Muzzarelli et al., EXS 1999; 87:251-264

[0050] Kratz et al., Scand. J. Plast. Reconstr. Surg. Hand Surg. 1997

I claim:
 1. A solution comprising an ionic chitosan iodine complex, saidsolution consisting essentially of: a. a cationic polymer comprisingchitosan or a derivative thereof; b. an aqueous vehicle; c. elementaliodine; and d. an iodide source.
 2. The solution of claim 1 wherein thechitosan or derivative thereof has a molecular weight of 10 to 100 KiloDalton.
 3. The solution of claim 1 wherein the chitosan or derivativethereof has a degree of deacetylation of 30% or more.
 4. The solution ofclaim 1 wherein the aqueous vehicle includes one or more of thefollowing acids: acetic, lactic, citric, glycolic, or their buffers orsalts.
 5. The solution of claim 4 wherein the pH value of the finalcomposition is between 3.0 and 8.0.
 6. The solution of claim 1 whereinthe chitosan iodide complex further comprises a non-volatile compoundcontaining two or more hydroxyl groups.
 7. The solution of claim 6wherein the non-volatile compound is from the group of ethylene glycol,propylene glycol, glycerol, sorbitol or polyethylene glycol, or thelike, at a concentration range between 5% and 25%.
 8. The solution ofclaim 1 wherein the concentration range of the elemental iodine is 0.05%to 1%.
 9. The solution of claim 1 wherein the iodide source ishydroiodic acid or potassium iodide or sodium iodide or the like. 10.The solution of claim 1 wherein the iodide source is present at aconcentration range of 0.05% to 1%.
 11. The solution of claim 1, whereinsaid solution is a pharmaceutically useful hydrogel.
 12. The solution ofclaim 1 wherein said hydrogel is used in treatment of wounds.
 13. Thesolution of claim 1 wherein said hydrogel is used to promote woundhealing.
 14. The solution of claim 1 wherein said hydrogel is used as adisinfectant for skin or other body surfaces or body cavities.
 15. Thesolution of claim 1 wherein the hydrogel is incorporated into bandages,films, sutures, or the like.
 16. A method for making an iodine chitosancomplex, said method comprising the steps of: a. dissolving chitosan ora derivative thereof in a portion of an aqueous vehicle to maintain oracquire positive charge; b. dissolving iodine and an iodide source in asecond portion of aqueous vehicle to maintain or acquire a negativecharge; and c. mixing the two portions of aqueous vehicle to form ahomogeneous composition.